Nicholas J. Short

Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

The impact of achieving complete molecular response (CMR) in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with Ph(+) ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR-ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P = .005) and relapse-free survival (RFS; P = .002) than did MRD status at CR (P = .11 and P = .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P = .009) and RFS (126 vs 18 months, respectively; P = .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P = .01). Patients with Ph(+) ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT.

Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis

The clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial.

Differential impact of minimal residual disease negativity according to the salvage status in patients with relapsed/refractory B‐cell acute lymphoblastic leukemia

Minimal residual disease (MRD) assessment predicts survival for patients with newly diagnosed acute lymphoblastic leukemia (ALL). Its significance in relapsed/refractory ALL is less clear.

Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini–Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial

Importance The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL. Objective To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL. Design, Setting, and Participants A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston. Interventions The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini–hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles. Main Outcomes and Measures The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate. Results Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03). Conclusions and Relevance The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates. Trial Registration clinicaltrials.gov Identifier: NCT01371630

Acute Myeloid Leukemia: Past, Present, and Prospects for the Future

Dose intensification of chemotherapy and the combination of a third cytotoxic agent with standard cytarabine and anthracycline-based induction chemotherapy have led to improved outcomes in select groups of patients with acute myeloid leukemia (AML). However, despite some progress in this area, it appears that we might be reaching the limit of cytotoxic chemotherapy for the treatment of AML, especially in older patients and in those with poor-risk features whose disease tends to be relatively chemoresistant. Recent advances in the molecular classification of AML have identified pathogenic pathways that can be exploited with targeted agents and rational drug combinations. Novel nontransplant immunotherapies also show promise in the treatment of AML, especially when a targetable molecular aberration cannot be identified. Sensitive methods for detecting minimal residual disease in AML have not only improved prognostication of these patients but also provide the framework for risk-adapted strategies in this heterogeneous disease.

Randomized phase 2 study of low-dose decitabine vs low-dose azacitidine in lower-risk MDS and MDS/MPN

Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m2 intravenously/subcutaneously daily or decitabine 20 mg/m2 intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% (P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine (P = .2). Cytogenetic response rates were 61% and 25% (P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively (P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225).

Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study

BACKGROUND Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody bound to a toxin, calicheamicin, has shown single-agent activity in relapsed or refractory acute lymphoblastic leukaemia. We aimed to assess the activity and safety of inotuzumab ozogamicin in combination with low-intensity chemotherapy in older patients with acute lymphoblastic leukaemia. METHODS We did a single-arm, phase 2 study at the MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 60 years or older and had newly diagnosed, Philadelphia chromosome-negative, acute lymphoblastic leukaemia, and an Eastern Cooperative Oncology Group performance status of 3 or lower. The induction chemotherapy regimen used was mini-hyper-CVD (a lower intensity version of the conventional hyper-CVAD). Odd-numbered cycles (1,3, 5, and 7) comprised intravenous cyclophosphamide (150 mg/m2 every 12 h on days 1-3) and oral or intravenous dexamethasone (20 mg per day on days 1-4 and days 11-14); no anthracycline was administered. Intravenous vincristine (2 mg flat dose) was given on days 1 and 8. Even-numbered cycles comprised intravenous methotrexate (250 mg/m2 on day 1) and intravenous cytarabine (0·5 g/m2 given every 12 h on days 2 and 3). Intravenous inotuzumab ozogamicin was given on day 3 of the first four cycles at the dose of 1·3-1·8 mg/m2 at cycle 1, followed by 1·0 -1·3 mg/m2 in subsequent cycles. Maintenance therapy with dose-reduced POMP (purinethol [6-mercaptopurine], oncovin [vincristine sulfate], methotrexate, and prednisone) was given for 3 years. The primary endpoint of this study was progression-free survival at 2 years. Analyses were by intention to treat. The study is ongoing, recruiting patients for an approved expansion phase with a modified treatment plan by protocol amendment. The trial is registered with ClinicalTrials.gov, number NCT01371630. FINDINGS Between Nov 12, 2011, and April 22, 2017, 52 patients with a median age of 68 years (IQR 64-72) were enrolled. With a median follow-up of 29 months (IQR 13-48), 2-year progression-free survival was 59% (95% CI 43-72). The most frequent grade 3-4 adverse events were prolonged thrombocytopenia (42 [81%] patients), infections during induction (27 [52%]) and consolidation chemotherapy (36 [69%]), hyperglycaemia (28 [54%]), hypokalaemia (16 [31%]), increased aminotransferases (ten [19%]), hyperbilirubinaemia (nine [17%]), and haemorrhage (seven [15%]). Veno-occlusive disease occurred in four (8%) patients. Six (12%) patients died from adverse events that were deemed treatment related (five [10%] from sepsis and one [2%] from veno-occlusive disease). INTERPRETATION Inotuzumab ozogamicin plus mini-hyper-CVD chemotherapy is a safe and active first-line therapy option in older patients with newly diagnosed acute lymphoblastic leukaemia and could represent a new therapy for this population. Randomised, phase 3 trials to evaluate the efficacy of this combination compared with the current standard of care in this setting, combination chemotherapy without inotuzumab ozogamicin, are warranted. FUNDING MD Anderson Cancer Center.

Prognostic impact of pretreatment cytogenetics in adult Philadelphia chromosome–negative acute lymphoblastic leukemia in the era of minimal residual disease

The introduction of novel prognostic factors such as minimal residual disease (MRD) and genomic profiling has led to the reevaluation of the role of cytogenetics and other conventional factors in risk stratification for acute lymphoblastic leukemia (ALL).

Safety and Efficacy of Blinatumomab in Combination with a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-Positive Leukemia

Micro‐Abstract The prognosis of patients with relapsed refractory Philadelphia chromosome–positive acute leukemia is considered poor. The combination of blinatumomab and a TKI resulted in high overall response rates among 13 patients. These results are promising and this strategy may minimize the use of chemotherapy in this setting. Objective: The treatment of Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia has been revolutionized with the introduction of tyrosine kinase inhibitors (TKIs) and the combination of these agents with chemotherapy. Blinatumomab is a bispecific anti‐CD3/CD19 monoclonal antibody with clinical activity as single‐agent in the relapsed setting and independent of BCR‐ABL1 mutational status, including T315I. The combination of blinatumomab with a TKI may further improve outcomes for this high‐risk population, including higher eradication of minimal residual disease and minimize the use of chemotherapy. Patients and Methods: We retrospectively studied 12 adults with relapsed/refractory Ph+ acute lymphoblastic leukemia (n = 9) and chronic myeloid leukemia in blast crisis (n = 3), treated with the combination blinatumomab and a TKI (ponatinib, n = 8; dasatinib, n = 3; bosutinib, n = 1). All patients have previously failed at least 1 line of chemotherapy, including allogeneic stem cell transplantation, and 1 class of TKIs. Patients were treated for either overt hematologic relapse (n = 6) or persistent minimal residual disease following other regimens (n = 6). Results: The complete hematologic, cytogenetic, and molecular response rates were 50% (3/6), 71% (5/7), and 75% (9/12), respectively. Two cases of grade 2 cytokine release syndrome were observed, all of which resolved with steroids and tocilizumab. No cardiovascular adverse events were encountered. With a median follow‐up of 8 months, the median survival was not reached; the 6‐month and 1‐year overall survival rates were 73%. Conclusions: The combination of blinatumomab with TKI is safe and effective in patients with relapsed/refractory Ph+ disease. Prospective studies are warranted.

Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor.

In patients with Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well‐established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first‐line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse‐free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or −9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor‐risk ACA group. Patients with one or more poor‐risk ACAs in the absence of HeH had significantly shorter RFS (5‐year RFS rate 33% versus 59%, P = 0.01) and OS (5‐year OS rate 24% versus 63%, P = 0.003). Poor‐risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor‐risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08‐3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10‐3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or −9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI.